Single-blind, within-block randomized, clean-air-controlled study to assess the effect of lactose and sodium chloride particles in patients with allergic rhinitis on nasal symptoms when challenged in the Fraunhofer Allergen Challenge Chamber

Allergen Challenge Chambers (ACC) are used worldwide since many years to test anti-allergic treatment in early clinical development. ACCs provide the advantage of controlled atmospheres with stable allergen load and highly reproducible symptoms during challenges.

The Fraunhofer ACC has been used since more than 20 years to test a range of different anti-allergic treatments, mostly using pollen challenges.

For house dust mite (HDM) challenges, a carrier solution containing lactose or sodium chloride is reconstituted with commercially available HDM allergen. The solution is spray-dried to create allergen loaded lactose or sodium chloride particles of a determined size. Those particles are distributed in the ACC.

Whether lactose or sodium chloride particles alone could induce nasal irritation during allergen challenges, has not been examined. Should allergen-free carrier solutions contribute to nasal symptoms, study results might be confounded. Even more so, if one carrier solution caused more nasal irritation than the other.

To determine if allergen-free carrier solutions alone irritate the nasal mucosa, we expose subjects with allergic rhinitis and house dust mite allergy to three different atmospheres: (1) lactose particles alone, (2) sodium chloride particles alone, and (3) clean air. Also, we aim to document nasal symptoms during challenges with HDM-containing carrier solutions to decide on the best carrier option for future clinical trials.

Inclusion Criteria:

1. Able and willing to give written informed consent.

2. Male and female subjects, aged 18-65 years. Women will be considered for inclusion if they are:

   • Not pregnant, as confirmed by pregnancy test (see flow chart), and not nursing.
   • Of non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is pre-menarchial or post-menopausal, with documented proof of hysterectomy or tubal ligation, or meets clinical criteria for menopause and has been amenorrhoeic for more than 1 year prior to the screening visit).
   • Of childbearing potential and using a highly effective method of contraception during the entire study (vasectomised partner, sexual abstinence - the lifestyle of the female should be such that there is complete abstinence from intercourse from two weeks prior to the first allergen challenge until at least 72 hours after the last allergen challenge -, implants, injectables, combined oral contraceptives, hormonal IUDs or double-barrier methods, i.e. any double combination of IUD, condom with spermicidal gel, diaphragm, sponge, and cervical cap).

3. Body mass index between 18 and 32 kg/m2

4. History of HDM-induced allergic rhinitis with or without conjunctivitis of 1 year or longer in duration at screening.

5. Positive skin prick test responses (positive wheal diameter reaction of ≥ 3 mm larger than the negative control and wheal diameter < 2 mm to the sodium chloride/diluent negative control) to D. pteronyssinus at screening or within the past 12 months (if performed and documented at the clinical unit).

6. Serum specific IgE level (≥ 0.7 kU/L) to D. pteronyssinus at screening or within the past 12 months (if performed and documented at the clinical unit).

7. FEV1 of 80% of predicted value or greater at screening. If subject fails to achieve this value, the assessment may be repeated 2 additional times.

8. Total Nasal Symptom Score (TNSS) of ≤ 3 prior to entering the chamber at visit 2.

9. Smokers or non-smokers.

Exclusion Criteria:

1. Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, urine analysis, vital signs, lung function or ECG at screening visit , which, in the opinion of the investigator, may either put the subject at risk because of participation in the study or may influence the results of the study, or the subject's ability to participate in the study.
2. Diastolic blood pressure above 95 mmHg.
3. Past or present disease, which as judged by the investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, hematological disease, neurological disease, endocrine disease or pulmonary disease (including but not confined to chronic bronchitis, emphysema, tuberculosis, bronchiectasis or cystic fibrosis).
4. History of an acute infection at screening that has not resolved four weeks prior to visit 2.
5. Nasal condition that could confound the efficacy or safety assessments (e.g., nasal polyps).
6. Concomitant allergies to seasonal aeroallergens which are anticipated to be or become active (i.e., grass, trees, weeds, rye; defined as IgE ≥ 3.5 kU/L [IgE samples drawn within 12 months prior to screening can be used to assess criteria as long as they are performed and documented at the clinical unit]; OR symptomatic to aeroallergens within the past 2 years or within the past 2 allergy seasons; OR both) through the completion of the study.
7. Concomitant allergy to an animal dander who has exposure on a regular basis to the respective animal dander.
8. History of allergic reactions such as anaphylactic shock, exanthema generalized, angioedema or hypotension caused by HDM and/or any medical products (including vaccine) in the past.
9. Known or suspected clinically relevant intolerance to lactose .
10. Asthma other than mild asthma which is treated with short acting beta-2-agonists only and which is controlled according to the current GINA guidelines.
11. Participation in another clinical trial 30 days prior to enrollment.
12. Donation of more than 400 ml of blood the preceding 2 months before screening.
13. History of regular drug or alcohol abuse in the past 3 months.
14. Risk of non-compliance with study procedures.
15. Suspected inability to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study.
16. Specific Immunotherapy (SIT) within five years prior to the study.
17. Treatment with medication that might interfere with rescue medication for anaphylactic reactions (e.g. beta blocker).
18. Systemic immunosuppression treatment (e.g. oral steroids, biologics, e.g. dupilumab, JAK-Inhibitors, cyclosporine, azathioprine, Mycophenolat Mofetil (MMF) within 3 months before visit 2
19. Treatment with anti-allergic medication or topical steroids (within 2 weeks before visit 2)

Patients are blinded to the sequence of exposures. Within the 2 blocks, the order of challenge atmospheres will be randomized.